11 alpha, 17 alpha, 21-trihydroxyallopregnane and its esters



Patented Nov. 17, 1953 UNITED. STATES P N -(O C d A 11liLrIia-1": A12 1??? ofi 2 William P. Schneider, Kalamazoo, Mich, as-

signor to The Upjohn Company,- Kalamazoo, Mich., a corporation of Michigan No Drawing. Application October 1, 1952,

Serial No. 312,660

4 Claims. (Cl. 260-3974) I This invention relates to a new compound, 11a,17a,21 trihydroxyallopregnane 3,20 dione and esters thereof, having pharmacological activity and utility in the synthesis of corticosterone, cortisone and other ll-oxygenated steroids. Anobject of this invention is to provide the novel 11a,17a,21 -trihydroxyallopregnane- 3,20 -dione and esters thereof.

The novel 11a,17a,2l-trihydroxyallopregnane- 3,20-dione offthe present invention may be represented by the following structural formula:

Example 1 .-'-11 ,1 7,21 -trihydro.ryallopregnane- 3,20-dione 2 The-mother liquor from the above recrystallization's was evaporated to dryness to leave a residue having a melting point of 1'75- to 195 degrees centigrade. A 21 '7-milligram portion of this residue was dissolved in fifty milliliters of acetone and chromatographed over 25 grams of a mixture of two parts of Celite diatomaceous earth and one part of DarcoG-GO activated carbon. Elution with a total of 800 milliliters of acetone gave 138 milligrams of 11a,17u.,21-t1ihydroxypregnane-3,20-dlone having a melting point of 195 to 207 degrees centigrade. Elution again with 600 milliliters of methylenechloride, and evaporation of the solvent from the eluate gave 56 milligrams of crude crystals having a melting point of 220 to 225 degrees centigrade.

Recrystallization twice from acetone gave 11a,1'la,21 trihydroxyallopregnane 3,20 dione having a melting point of 228 to 230 degrees centigrade. Infrared spectra showed this .allo isomer to be different from the normal isomer obtained above, and the curve was consistent with that expected for the allo isomer.

A mixture of 800 milligrams of 11,17,21-tri- .11,l7,21-trihydroxypregnane- 0-dione having a melting point of 220 to 222 degrees centigrade. Analysia-Calculated for C21H 2Os: C, 69.20; H, 8.85. Found: C, 69.07; H, 8.61.

AnaZysis.-Calculated for C21H32O5: C, 69.20; H, 8.85. Found: C, 68.83; H, 8.52.

The 11a.,17a,21 trihydroxyallopregnane 3,20- dione of this invention is useful in the synthesis of the physiologically active adrenosterone. For example, oxidation of l1a,17,2l-trihydroxyallopregnane-3,20-dione with chromium trioxide in acetic acid splits off the side chain and oxidizes the eleven hydroxyl group to a ketone to give 3,11,1'7-androstantrione which can be converted to adrenosterone according to the procedure of Djerassi et al., J. Am. Chem. Soc., 72, 4077 (1950). The 11a,17a,21 trihydroxyallopregnane 3,20- dione and esters of this invention demonstrate pharmacological and hormonal activity including inhibitory cortisone activity.

Novel esters of l1,17a,21-trihydroxyallopregnane-3,20-dione may also be prepared. The starting 11,17,21-trihydroxyal1opregnane-3,20- dione is admixed with an acylating agent such as, for example, ketene, a ketene of a selected acid, an acid, acid chloride or acid anhydride, or other known acylating agent, usually in a solvent such as, for example, pyridine or the like, or an inert solvent, including solvents like benzene, toluene, ether, and the like, for example, and heated at a temperature between about zero degrees centigrade and the boiling point of the reaction mixture, usually about room temperature, for a period between about a half hour and about 96 hours. The time of reaction as well as the temperature at which the reaction is carriedout, the

methylene chloride solution 01' product.

' acyiating agent, and the ratio of reactants may be varied. The reaction mixture is suitably poured into ice or cold water, the product collected in an appropriate solvent which is thereafter washed with successive portions of a mildly basic solution and water to obtain a solution which is essentially neutral.

In some instances, the product may crystallize from the reaction mixture, in which case it may be advantageous to separate the product by filtration or other means, wash with water, and thereafter purify by conventional means, such as, for example, by recrystallization from a suitable solvent or by chromatographic purification. as

.deemed necessary.

The thus-described acylation process, which is illustrated in more detail in the example following in this specification, produces both the monoesters and the di-esters, although in diil'erent proportions, depending upon the proportions of acylating agent to 11a,1'7,21-trihydroxyallopregnane-3,20-dione. Using approximately one equivalent of acyiating agent to said steroid produces predominantly the mono-acylated product, whereas with about two or more equivalents of acylating agent to said steroid, the predominant product is the diacylated product.

Example 2.1 1 a,21 -diacetoa:y-1 7a-hydroxyallopregnane-3,20-dione '4 by distilling the acetic anhydride,-acetic acid, and pyridinei'rom the reaction mixture at reduced pressure and crystallizing the distillation residue from the methylene chloride.

In a similar manner, other esters of 11a,- 17a,21 trihydroxyallopregnane 3,20 dione are prepared according to the described acylation procedures. Representative esters of 11a,17a,21- trihydroxyallopregnane 3,20 dione thus prepared include one to eight carbon atom carboxylic acid acyloxy esters of saturated or unsaturated, aliphatic, carbocyclic, or cycloaliphatic, aryl, aryl-alkyl, alkaryl, mono, di or polycarboxylic acids which form ester groups such as, for example, iformyloxy, acetoxy, propionyloxy, dimethylacetoxy, trimethylacetoxy, butyryloxy,

valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoxy, phenylacetoxy, toluoyloxy, napthoyloxy, cyclopentyliormyloxy, B-cyclopentylpropionyloxy, acrylyloxy, cyclohexylformyloxy, the half and di-esters oi malonic, maleic, succinic, glutaric and adipic acids, and the like. The acids may also contain non-interfering substituents, such as mono or poly halo, chloro, bromo, hydroxy, methoxy, and the like, if desired.

We claim:

1. A compound selected from the group consisting of 11a,17a 21-trihydroxyallopregnane- 3,20-dione and its esters of hydrocarboncarboxylic acids having from one to eight carbon atoms inclusively.

2. 11a,17a,21 trihydroxyallopregnane. 3,20- dione esters of hydrocarbon-carboxyiic acids having from one to eight carbon atoms inclusively.

3. 11,21 diacetoxy-l'la-hydroxyallopregnane- 3,20-dione.

4. 1'1a,17a,21 trihydroxyallopregnane 3,20-

dione.

WILLIAM P. SCHNEIDER.

References Cited in the file 01' this patent UNITED STATES PATENTS Name Date Murray et a1 July 8, 1952 Number 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 11A,17A,21-TRIHYDROXYALLOPREGNANE3,20-DIONE AND ITS ESTERS OF HYDROCARBONCARBOXYLIC ACIDS HAVING FROM ONE TO EIGHT CARBON ATOMS INCLUSIVELY. 